Chronic obstructive pulmonary disease (COPD) includes both emphysema and small airway disease. COPD has typically been defined based on a reduction in the FEV1/FVC ratio, with the severity of COPD determined by the level of reduction in the FEV1. However, a large number of subjects with reduced FEV1 have a normal FEV1/FVC, which is an unclassified spirometric pattern. There are likely multiple etiologies in this group including well-known restrictive processes (e.g. interstitial lung disease, obesity) and COPD which does not meet classic spirometric definitions. We hypothesize that a subset of unclassified spirometry subjects have COPD which can be determined based on radiologic and genetic studies. Participants in the COPDGene Study with unclassified spirometry will undergo chest CT scans, which will be assessed for emphysema and airway disease using quantitative analysis. Epidemiological relationships between emphysema and airway disease with gender, race, and body mass index will be assessed. Genotyping of a panel of SNPs that have been significantly associated with COPD in genome-wide association studies will be performed, and population-based genetic association analysis will determine whether these SNPs also influence spirometric and CT phenotypes in the unclassified spirometry group. Finally, cluster analysis of the CT, physiological, and epidemiological data will be performed, and genetic association analysis using these clusters will determine whether a COPD subset of the unclassified spirometry group can be identified. Subjects with an unclassified spirometric pattern represent a large and understudied population, which likely includes a substantial number of subjects with COPD that do not meet classic spirometric criteria for COPD. We will apply state-of-the-art imaging and genetic methods to identify a subset of unclassified spirometry subjects with COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) includes both emphysema and small airway disease. COPD is usually defined based on a breathing test called spirometry, which measures the amount of air that can be blown out during a forced expiration (FVC) and the amount of air blown out during the first second of that expiration (FEV1). COPD subjects have a reduced FEV1/FVC ratio, with the severity of COPD determined by the level of reduction in the FEV1. However, a large number of subjects with reduced FEV1 have a normal FEV1/FVC (unclassified spirometric pattern), and there are likely multiple causes for the breathing problems in this group including well-known restrictive processes (e.g. interstitial lung disease, obesity) and COPD which does not meet classic spirometric definitions. We will use chest CT scans and genetic studies to identify the subset of unclassified spirometry subjects that have emphysema and/or small airway disease, so that those individuals can be treated more effectively.